Network Evolution Statistics of Networks Comparing Networks Networks in Cellular Biology A....

Network EvolutionStatistics of Networks

Comparing Networks

Networks in Cellular Biology

A. Metabolic Pathways

B. Regulatory Networks

C. Signaling Pathways

D. Protein Interaction Networks - PIN

Empirical Facts

Dynamics on Networks (models)

Models of Network Evolution

Network Alignment & MotifsBarabasi & Oltvai, 2004, Sharan & Ideker, 2006

•Motifs

•Network Alignment

1. Are nodes/edges labelled?2. Which operations are allowed?3. Pair/Multiple?

•Network Search

Find (approximately) a network within a set of others.

•Network integration

Combine a set of networks to one large network.

Network Description and Statistics IBarabasi & Oltvai, 2004

Remade from Barabasi, 2004

•Degree Distribution - P(k)

•Scale Free Networks P(k)~k-

•Hubs: multiply connected nodes

The lower , the more hubs.

Small World Property:

Graph connected and path lengths small

•Degree/Indegree/Outdegree

•Shortest Path

•Mean Path Length

•Diameter:

•Clustering Coefficient - CI=2TI/nI(nI-1)

CA=1/10

Maxi, j{Dist(i, j)}

Dist(i, j)

Network Description and Statistics IIBarabasi & Oltvai, 2004

C.Hierarchial

Copy smaller graphs and let them keep their connections.

Phase transition:

Connected if:

A. Random Networks [Erdos and Rényi (1959, 1960)]

Mean path length ~ ln(k)

B. Scale Free [Price,1965 & Barabasi,1999]

Preferential attachment. Add proportionally to connectedness

Mean path length ~ lnln(k)

A. Metabolic Pathways

S P

I2

I4

I3

I1

•Flux Analysis

•Metabolic Control Theory

•Biochemical Systems Theory

•Kinetic Modeling

Control Coefficients(Heinrich & Schuster: Regulation of Cellular Systems. 1996)

Flux Control Coeffecient – FCC:

)ln(

)ln()( 0

k

j

k

j

j

kE

k

j

j

kJE E

J

E

J

J

E

E

J

J

EC

k

j

k

Kacser & Burns, 73

)ln(

)ln()( 0

k

j

k

j

j

kv

k

j

j

kJ JJ

J

J

JC

k

j

k

Heinrich & Rapoport, 73-74

Flux Jj (edges) – Enzyme conc., Ek (edges), S – internal nodes.

P1 S1 P2

E,

FCF: gluconeogenesis from lactate

Pyruvate transport .01

Pyruvate carboxylase .83

Oxaloacetate transport .04

PEOCK .08

A Model for Network Inference

•A core metabolism:

•A given set of metabolites:

•A given set of possible reactions -

arrows not shown.

•A set of present reactions - M

black and red arrows

Let be the rate of deletion the rate of insertionThen

Restriction R:

A metabolism must define a connected graph

M + R defines

1. a set of deletable (dashed) edges D(M):

2. and a set of addable edges A(M):

dP(M)

dt P(M ') P(M ' ')

M ''A (M )

M 'D(M )

- P(M)[ D(M) A(M) ]

Likelihood of Homologous PathwaysNumber of Metabolisms:

1 2

3 4

+ 2 symmetrical versions

P( , )=P( )P( -> )

Eleni Giannoulatou

Approaches: Continuous Time Markov Chains with computational tricks.

MCMC

Importance Sampling

Remade from Somogyi & Sniegoski,96. F2

A B

A BmRNA mRNAFactor A Factor B

A B

A B

C

C

A B

A B

C

C

mRNA

mRNA

Factor C

Factor B

mRNAFactor A

mRNA

mRNA

Factor C

Factor B

mRNAFactor A

B. Regulatory Networks

Remade from Somogyi & Sniegoski,96. F4

Boolen functions, Wiring Diagrams and Trajectories

A B

A B

C

C

Inputs 2 1 1Rule 4 2 2

A activates B

B activates C

A is activated by B, inhibited by (B>C)

Point Attractor

A B C1 1 01 1 10 1 10 0 10 0 00 0 0

2 State Attractor

A B C1 0 00 1 01 0 10 1 0

Contradiction: Always turned off (biological meaningless) Tautology: Always turned on (household genes)

k=1:

input

output

0

10 or 1

4k=2:

input

output

0,0

0,1

1,0

1,1

0 or 1

16

For each gene dependent on i genes: genes.dependent of choices

i

kki

i

k)2 ( Rules BooleanofNumber

A single function:

k2kk2

The whole set:

Gene 2

Gene n

Gene 1

Time 1 Time 2 Time 3 Time T

Boolean NetworksR.Somogyi & CA Sniegoski (1996) Modelling the Complexity of Genetic Networks Complexity 1.6.45-64.

Reverse Engeneering Algorithm-RevealD’haeseler et al.(2000) Genetic network Inference: from co-expression clustering to reverse engineering. Bioinformatics 16.8.707-

Assumptions:

Discrete known Generations

No Noise

0 1 1 1 1 0

0 0 1 1 0 1

1 1 1 0 1 0

BOOL-1Akutsu et al. (2000) Inferring qualitative relations in genetic networks and metabolic pathways. Bioinformatics 16.2.727-

If O(22k[2k + ]log(n)) INPUT patterns are given uniformly randomly, BOOL-1 correctly

identifies the underlying network with probability 1-n, where is any fixed real number > 1.

Algorithm

For each gene do (n)

For each boolean rule (<= k inputs) not violated, keep it.

C. Signaling Pathways

www.hprd.org from Pierre deMeyts

•Transmits signals from membrane to gene regulation.

•Its function is enigmatic as some of the molecules involved are common to different functions and how cross-interaction is avoided is unknown.

D. Protein Interaction Network

Yea

st p

rote

in in

tera

ctio

n n

etw

ork

[Je

on

g e

t al

., N

atu

re (

20

01

)]•The sticking together of different protein is measured by mass spectroscopy.

•The nodes will be all known proteins.

•Two nodes are connected if they stick together. This can be indicator of being part of a a functional protein complex, but can also occur for other reasons.

PIN Network EvolutionBarabasi & Oltvai, 2004 & Berg et al. ,2004; Wiuf etal., 2006

•A gene duplicates

•Inherits it connections

•The connections can change

Berg et al. ,2004:

•Gene duplication slow ~10-9/year

•Connection evolution fast ~10-6/year

•Observed networks can be modeled as if node number was fixed.

Likelihood of PINsIrreducible (and isomorphic)

Data

de-DAing

De-con

nectin

g

2386 nodes and 7221 links

735 nodes

)0,33,.66,.1(0

•Can only handle 1 graph.

•Limited Evolution Model